The chemistry of L-ascorbic acid derivatives in the asymmetric synthesis of C2- and C3-substituted aldono-gamma-lactones

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The antioxidant and redox properties of L-ascorbic acid are closely associated with the electron rich 2, 3-enediol moiety of the molecule and therefore selective functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity studies. Reactions of 5- and 6-OH protected ascorbic acid with electrophilic reagents exclusively produce the corresponding 3-O-alkylated products under mild basic conditions due to the high nucleophilicity of the C-3-OH. Based on the density functional theory (B3LYP) electron density calculations, a novel and general method was devised for the direct alkylation of the 2-OH group of ascorbic acid with complete regio- and chemo-selectivity. A complete spectroscopic analysis of two complementary series of 2- O -acetyl-3- O -alkyl and 2- O -alkyl-3- O -acetyl ascorbic acid derivatives was carried out to define their spectroscopic characteristics and to resolve common inconsistencies in the literature.
The asymmetric approach to the synthesis of natural products or other biologically active compounds is impeded by low abundance of natural sources as well as a limited number of efficient synthetic methods. Nevertheless, carbohydrate-based systems such as the aldono-1,4-lactones (also known as aldono-γ-lactones) which generate a host of chiral compounds have been particularly rewarding in this respect. This study shows a practical approach using 5,6- O -isopropylidene-L-ascorbic acid (ketal of L-ascorbic acid) as a single common starting material for facile asymmetric synthesis of protected, optically pure and functionalized aldono-1,4-lactones derivatives, valuable in the synthesis of derivatives of various pharmacologically active agents for structure-activity studies. The practicality of this new approach is demonstrated by the convenient synthesis of a series of thermal Claisen-rearranged products of 5,6- O -isopropylidene-3- O -allyl-L-ascorbic acid and 5,6- O -isopropylidene-2- O -allyl-L-ascorbic acid as the corresponding 5,6- O -isopropylidene-2-allyl-3-keto-L-galactono-γ-lactone and 5,6- O -isopropylidene-3-allyl-2-keto-L-galactono-γ-lactone respectively. The synthetic routes are economical, efficient, diastereospecific, and proceed in high yields.

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"August 2005."

Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry.